T55 - The Genetic Basis Of The Comorbidity Between Cannabis Use And Major Depression

Abstract

While the prevalence of major depression is known to be elevated amongst cannabis users, the causes of this comorbidity are not clear. Here we investigate the role of genetics in this relationship and identify genomic loci linked to these traits. Using a sample of Mexican American extended families (n=1,284), we use variance decomposition methods to establish the degree of genetic correlation between cannabis use and major depression. Genome-wide univariate and bivariate linkage scans are conducted to localize the chromosomal regions influencing these traits and the comorbidity observed between them. Both major depression (h2=0.349, p=1.06x10-5, SE=0.100) and cannabis use (h2=0.614, p=1.00x10-6, SE=0.151) are heritable traits, and there is significant genetic correlation between the two (ρg=0.424, p=0.0364, SE=0.195). Genome-wide linkage scans identify a significant univariate linkage peak for major depression on chromosome 22 (LOD=3.144 at 2cM), with a suggestive peak for cannabis use on chromosome 21 (LOD=2.123 at 37cM). A significant pleiotropic linkage peak influencing both major depression and cannabis use was identified on chromosome 11, using a bivariate model (LOD=3.229 at 112cM). This location spans the NCAM1-TTC12-ANKK1-DRDR2 gene cluster. Follow-up of this pleiotropic signal provided tentative evidence implicating a rare SNP 20kb upstream of NCAM1 (s7932341); with peak-wide significant bivariate association with cannabis use and major depression (p=3.10x10-5). We show that genetic influences play an important role in the comorbidity between cannabis use and major depression.Specifically, we identify a pleiotropic locus on chromosome 11, spanning the NCAM1-TTC12-ANKK1-DRDR2 gene cluster, which has been previously implicated in both addiction and depression research.